It is known that 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b]-[1,5]-benzodiazepine, also known as olanzapine (INN), is a drug widely used for the treatment of psychotic conditions.
Olanzapine as a base was described the first time in EP No. 454,436. In the specification a great number of inorganic and organic acids are mentioned as acids that can be used for salt formation, including hydrochloric acid. However, only the preparation of the olanzapine base is exemplified, no salt of olanzapine is characterized by physical-chemical parameters (e.g. melting point), and no process is disclosed for the preparation of any salt. Said patent specification is completely silent in mentioning any crystal form of the olanzapine base. There is not even a hint in the specification at the crystalline form of olanzapine base.
European Patent No. 733,635 discloses and claims polymorph form II olanzapine base. According to this specification olanzapine base prepared as specified in EP 454,436 is unstable, unsuitable for the preparation of pharmaceutical formulations and thus cannot be put on the market. According to this document the new olanzapine base of crystalline form II is sufficiently stable. Olanzapine base prepared as specified in EP 454,436 is designated as polymorph I.
Crystalline modifications of olanzapine base formed with one mole of methanol, one mole of ethanol and one mole of 1-propanol are disclosed and claimed in European Patent No. 733,634. This document is concerned with the crystalline monomethanol, monoethanol and mono-1-propanol solvates of olanzapine. The advantage of these crystalline solvates over the olanzapine base prepared according to EP 454,436 resides in the fact that by using methanol, ethanol or 1-propanol the product can be prepared in much higher purity, and only a single recrystallization is necessary during the purification.
Polymorph forms III, IV and V of olanzapine are described and claimed in WO 01/47933. These forms are prepared by dissolving olanzapine base in a mixture of acetic acid, formic acid or hydrochloric acid and water, neutralizing the acidic solution with ammonium hydroxide or sodium hydroxide and isolating the separating polymorph. According to the specification the advantage of polymorphic forms III, IV and V of olanzapine is that during the reaction carried out in a medium free of solvent a solvate-free product containing only a negligible amount of residual solvent can be obtained.
European Patent No. 831,098 discloses and claims crystalline modifications B, D and E of olanzapine dihydrate. According to the specification olanzapine dihydrates prepared in aqueous medium are intermediates of the polymorph form II olanzapine provided in EP No. 733, 635, which can be converted into polymorph form II olanzapine by vacuum drying carried out at a temperature between 40° C. and 70° C. The advantage of this process is that the anhydrous polymorphic crystalline form II, which is considered to be the most stable crystalline form, can be prepared via olanzapine dihydrate intermediate in an environmentally advantageous manner.
Crystalline modifications of olanzapine formed with dichloromethane are described and claimed in U.S. Pat. No. 5,637,584. According to this document olanzapine can be present in two anhydrous polymorphic forms. One of them, the polymorph designated as form II is metastable, consequently unsuitable for the preparation of pharmaceutical preparations, while the polymorph designated as form I is stable and suitable for pharmaceutical use in every respect. According to the specification the solvate of olanzapine formed with dichloromethane can be used for the preparation of anhydrous polymorphic form I olanzapine.
From the above references it is apparent that the production of anhydrous and stable olanzapine encounters serious difficulties. Olanzapine base forms solvates readily with water or solvents, consequently the preparation of crystalline olanzapine suitable for pharmaceutical use with regard to the residual solvent content is problematical.